Stable compositions for parenteral administration and their use

Abstract

The invention relates to certain stable microsphere compositions containing a fat, a wax or a mixture thereof; an active ingredient selected from LL-F28249α-λ compounds, 23-oxo or 23-imino derivatives of LL-F28249α-λ compounds, milbemycin compounds and avermectin compounds; an antioxidant and, optionally, an oil, a semi-soft fat, a fatty acid derivative or mixture thereof. The invention also relates to a method for introducing and maintaining levels of the active compound in the blood of warm-blooded animals for extended periods of time and for the prevention or treatment of infections and infestations caused by helminths, nematodes, acarids and endo- and ectoparasitic arthropods in warm-blooded animals by the parenteral administration of compositions of the invention.

We claim:  
     
       1. A microsphere composition comprising on a weight basis about 20% to 95% of a higher melting fat, a wax or a mixture thereof; about 1% to 50% of a compound dissolved into said higher melting fat, wax or mixture thereof, said compound selected from the group consisting of an LL-F28249α-λ, a 23-oxo or 23-imino derivative of an LL-F28249α-λ, a inilbemycin and an avermectin; 0 to about 30% of an oil, a semi-soft fat, a lower melting fatty acid, a lower melting fatty acid alcohol, a lower melting fatty acid ester, a lower melting fatty acid ether, a salt of a lower melting fatty acid or a mixture thereof; and about 0.001% to 10% of an antioxidant. 
     
     
       2. The microsphere composition according to  claim 1  comprising on a weight basis about 50% to 90% of the higher melting fat, the wax or the mixture thereof; about 5% to 25% of the compound; 0 to about 20% of the oil, the semi-soft fat, the lower melting fatty acid, the lower melting fatty acid alcohol, the lower melting fatty acid ester, the lower melting fatty acid ether, the salt of the lower melting fatty acid or the mixture thereof; and about 0.01% to 5% of the antioxidant. 
     
     
       3. The microsphere composition according to  claim 2  wherein the compound is 23-(O-methyloxime)-LL-F28249α. 
     
     
       4. The microsphere composition according to  claim 2  wherein the compound is LL-F28249α. 
     
     
       5. The microsphere composition according to  claim 2  wherein the higher melting fat is glyceryl tristearate, the oil is a neutral triglyceride oil and the antioxidant is butylated hydroxytoluene. 
     
     
       6. The microsphere composition according to  claim 2  wherein the composition further comprises on a weight basis about 0.1% to 20% of a surfactant, a salt, a buffer or a mixture thereof. 
     
     
       7. The microsphere composition according to  claim 2  wherein the weight average particle of the microsphere composition is in a range of about 25 microns to 300 microns. 
     
     
       8. The microsphere composition according to  claim 2  further comprising a pharmaceutically and pharmacologically acceptable liquid vehicle in which the microspheres are dispersed for parenteral administration and slow release. 
     
     
       9. A method for protecting or treating warm-blooded animals against infection or infestation by helminths, nematodes, acarids or endo- or ecto-parasitic arthropods which comprises parenterally administering to the animal a microsphere composition comprising on a weight basis about 20% to 95% of a higher melting fat, a wax or a mixture thereof; about 1% to 50% of a compound selected from the group consisting of an LL-F28249α-λ, a 23-oxo or 23-imino derivative of an LL-F28249α-λ, a milbemycin and an avermectin; 0 to about 30% of an oil, a semi-soft fat, a lower melting fatty acid, a lower melting fatty acid alcohol, a lower melting fatty acid ester, a lower melting fatty acid ether, a salt of a lower melting fatty acid or a mixture thereof; and about 0.001% to 10% of an antioxidant; wherein the microsphere is dispersed in a pharmaceutically and pharmacologically acceptable liquid vehicle. 
     
     
       10. The method according to  claim 9  wherein the microsphere comprises on a weight basis about 50% to 90% of the higher melting fat, the wax or the mixture thereof; about 5% to 25% of the compound; 0 to about 20% of the oil, the semi-soft fat, the lower melting fatty acid, the lower melting fatty acid alcohol, the lower melting fatty acid ester, the lower melting fatty acid ether, the salt of the lower melting fatty acid or the mixture thereof; and about 0.01% to 5% of the antioxidant. 
     
     
       11. The method according to  claim 10  wherein the compound is LL-F28249α or 23-(O-methyloxime)-LL-F28249α. 
     
     
       12. The method according to  claim 10  wherein the higher melting fat is glyceryl tristearate, the oil is a neutral triglyceride oil, the antioxidant is butylated hydroxytoluene, and the microsphere vehicle is a methylcellulose and saline mixture. 
     
     
       13. The method according to  claim 10  wherein the microsphere additionally comprises on a weight basis about 0.1% to 20% of a surfactant, a salt, a buffer or a mixture thereof. 
     
     
       14. The method according to  claim 10  wherein the weight average particle size of the microsphere composition is in a range of about 25 microns to 300 microns. 
     
     
       15. The method according to  claim 9  wherein the warm-blooded animal is selected from the group consisting of dogs, cats, cattle, sheep, horses, swine, poultry and goats. 
     
     
       16. A method for introducing and maintaining blood levels of a compound selected from the group consisting of an LL-F28249α-λ, a 23-oxo or 23-imino derivative of an LL-F28249α-λ, a milbemycin and an avermectin in a warm-blooded animal which comprises parenterally administering to the animal a microsphere composition comprising on a weight basis about 20% to 95% of a higher melting fat, a wax or a mixture thereof; about 1% to 50% of the compound; 0 to about 30% of an oil, a semi-soft fat, a lower melting fatty acid, a lower melting fatty acid alcohol, a lower melting fatty acid ester, a lower melting fatty acid ether, a salt of a lower melting fatty acid or a mixture thereof; and about 0.001% to 10% of an antioxidant; wherein the microsphere is dispersed in a pharmaceutically and pharmacologically acceptable liquid vehicle. 
     
     
       17. The method according to  claim 16  wherein the microsphere comprises on a weight basis about 50% to 90% of the higher melting fat, the wax or the mixture thereof; about 5% to 25% of the compound; 0 to about 20% of the oil, the semi-soft fat, the lower melting fatty acid, the lower melting fatty acid alcohol, the lower melting fatty acid ester, the lower melting fatty acid ether, the salt of the lower melting fatty acid or the mixture thereof; and about 0.01% to 5% of the antioxidant. 
     
     
       18. The method according to  claim 17  wherein the compound is LL-F28249α or 23-(O-methyloxime)-LL-F28249α. 
     
     
       19. The method according to  claim 17  wherein the higher melting fat is glyceryl tristearate, the oil is a neutral triglyceride oil, the antioxidant is butylated hydroxytoluene, and the microsphere vehicle is a methylcellulose and saline mixture.